Normal breast epithelial growth and differentiation is under the control of two well-studied molecular signaling pathways mediated by the epithelial growth factor (ERBB) and transforming growth factor (TGF-B.) receptor families. These pathways are also closely intertwined in the etiology of benign proliferative breast disease and breast cancer. The overall objective of this study is to identify predictors of breast cancer by investigating how genetic variation within the well-defined interacting ERBB and TGF-B signaling pathways interact with histologically defined breast lesions to affect breast cancer risk. We approach this objective by comprehensively studying a unique cohort of 7,923 women who underwent biopsy for benign breast disease, 529 of whom have developed invasive breast cancer or ductal carcinoma in situ during follow-up. The cohort is accompanied by epidemiological data of established breast cancer risk factors, paraffin-embedded tissue blocks of the initial benign breast disease biopsy, and rigorous pathologic detail of both the initial biopsy and subsequent tumor. We will conduct nested case-control studies on these patients. We also seek to perform an accurate whole genome amplification, which will provide an inexhaustible resource for investigating interactions between benign histology and other genetic traits. This cohort is being expanded through a separate R01 grant. We expect that over the next five years our nested case control study will expand to 890 cases and 1780 controls. Our specific aims are as follows: 1. To determine how genes that control ERBB signaling interact with each other and with benign breast disease to affect breast cancer risk. This Aim will focus on genes central to the ERBB signaling pathway. We will investigate the pathway in 600 cases and 1200 controls. We will apply LD mapping using efficient tagging SNPs to capture genetic diversity of each locus. 2. To determine how polymorphisms in genes central to the TGF-B signaling pathways interact with each other and with benign breast disease to affect breast cancer risk. The approach will follow that of Aim 1. 3. To define all variants in full linkage disequilibrium and that directly mark each haplotype significantly associated with progression to breast cancer. The narrow subset of these genetic variants, among all others at the gene, is a set of candidates that may be etiologically associated with breast cancer.